The overall focus of this PPG is on autonomic and vascular mechanisms engaged by low skeletal muscle oxygen tension, and their role in disease. The goal of Project 4 is to examine the effects of acute and intermittent hypoxic stress, two fundamental and prevalent types of physiologic stress, on circulatory control. Hypoxia is common in smokers, and intermittent hypoxia is characteristic of obstructive sleep apnea. Regional skeletal muscle hypoxia (ischemia) is also present during exercise and is pronounced in peripheral arterial disease. All of these conditions are marked by increased cardiovascular risk. It is well established that hypoxia and ischemia exert their effects on the circulation via integrated and at times competing influences on the autonomic nervous system and local metabolic control. Preliminary data from our laboratory demonstrate that in healthy humans intermittent hypoxia leads to sustained sympathetic activation. Because the antioxidant ascorbic acid attenuates the sympathoexcitatory effect of intermittent hypoxia, oxidative stress may be involved. We also found that sympathetic reflex responses to hypoxia are enhanced in patients with sleep apnea and are normalized in part by continuous positive airway pressure therapy. Similarly, in preliminary studies, ascorbic acid appears to attenuate the chemoreflex sensitizing effect of intermittent hypoxia in healthy humans. Despite chronically increased sympathetic activity, the vasodilation induced by acute hypoxia appears to be largely preserved in patients with sleep apnea. Collectively, these findings support the central hypothesis that intermittent hypoxia alters sympathetic activity and reflex function, and evokes compensatory peripheral vascular adaptations, possibly via oxidative stress. The specific aims of this proposal are to determine whether: (1) experimental intermittent hypoxia alters sympathetic reflex function, and whether this effect can be prevented by ascorbic acid; (2) skeletal muscle vascular adaptations to hypoxic stress are in part dependent on enhanced endothelium-derived hyperpolarizing factor, and is characteristic of nitric oxide deficient states due to enhanced oxidative stress; (3) cigarette smoking is associated with altered neurocirculatory control due to enhanced oxidative stress and is restored in part with ascorbic acid; and (4) reflex vasoconstrictor mechanisms are altered in peripheral arterial disease and act to restrict collateral blood flow in the ischemic limb. The proposed studies expand the scope of our prior work on neurocirculatory regulation during hypoxia and will provide new insight into the mechanisms that link intermittent hypoxia to adverse cardiovascular outcomes.